Cellular pharmacokinetics of daunorubicin: Uptake by leukaemic cells in vivo and fate

Summary In 6 patients with acute myeloblastic leukaemia, daunorubicin was assayed in leukaemic cells from peripheral blood or bone marrow. The cells were separated from red blood cells and granulocytes by centrifugation on a Ficoll-Isopac gradient. The assay was performed by high performance liquid chromatography. Daunorubicin concentrations in peripheral leukaemic cells, 2 hours after the end of the infusion, were much higher than in plasma, the cell/plasma concentration ratio reaching about 350 and rising to almost 700 at 24 h. At that time, drug concentrations were even higher in the bone marrow leukaemic cells. The value of the assay of daunorubicin in cells as method for monitoring therapy is discussed.     

Studies on pharmacokinetics and tissue distribution of bifendate nanosuspensions for intravenous delivery

It is reported that the nanosuspension is one of the promising formulations for poorly water-soluble drugs. In order to enhance the in vitro and in vivo behaviours of DDB (bifendate), DDB-NSP (DDB nanosuspensions) have been produced by the precipitation-combined micro?uidization method. The optimized DDB-NSP were transformed into dry powders by freeze-drying and then investigated by transmission electron microscopy, laser diffraction and X-ray diffraction (XRD) experiments. Next, the pharmacokinetics and biodistribution of DDB-NSP and DDB-Sol (DDB solution) were carried out. XRD experiments manifested that the crystalline state of DDB was preserved after the size reduction process. An accelerated dissolution velocity and increased saturation solubility could be shown for the DDB-NSP. Compared with DDB-Sol, DDB-NSP exhibited a markedly different pharmacokinetic property with a 17.18-fold increase in AUC_0–∞. Meanwhile, the tissue distribution demonstrated that DDB-NSP were mainly uptaken by RES organs particularly by liver. These results supported the fact that nanosuspension, as a promising intravenous drug-delivery system for DDB, could be developed as an alternative to the conventional DDB preparations.     

Synthesis and anti‐inflammatory activity of diversified heterocyclic systems

In continuation with our research program on the development of novel bioactive molecules, we report herein the design and synthesis of a series of diversified heterocycles ( 4 – 22 ). The synthesized compounds were evaluated for their anti‐inflammatory activity. The chemical structures of the newly synthesized compounds have been confirmed by NMR, FTIR, and microanalysis.     

Synthesis and pharmacological evaluation of 3‐(4‐chloro phenyl)‐2‐substituted‐3H‐quinazolin‐4‐ones as analgesic and anti‐inflammatory agents

A new series of 3‐(4‐chloro phenyl)‐2‐substituted‐3H‐quinazolin‐4‐ones were synthesized by reacting the amino group of 2‐hydrazino‐3‐(4‐chloro phenyl)‐3H‐quinazolin‐4‐one with different aldehydes and ketones. The compounds were investigated for their analgesic activity in albino mice, and for their anti‐inflammatory and ulcerogenic activities in Wistar rats. All test compounds exhibited analgesic and anti‐inflammatory activities. Compound VA2 (2‐(1‐ethylpropylidene‐hydrazino)‐3‐(4‐chloro phenyl)‐3H‐quinazolin‐4‐one) showed moderately more potent analgesic activity and compound VA3 (2‐(1‐methylbutylidene‐hydrazino)‐3‐(4‐chlorophenyl)‐3H‐quinazolin‐4‐one) showed moderately more potent anti‐inflammatory activity when compared with the reference standard, diclofenac sodium. The test compounds showed only mild ulcerogenic side effects when compared with aspirin. Drug Dev Res 69: 226–233, 2008 ©2008 Wiley‐Liss, Inc.     

One pot multi‐component synthesis of functionalized spiropyridine and pyrido[2,3‐d]pyrimidine scaffolds and their potent in‐vitro anti‐inflammatory and anti‐oxidant investigations

A new series of functionalized fused pyridines 4(a–i) and fused pyrido[2,3‐d]pyrimidines 8(a–c) were designed and synthesized through a multi‐component reaction where in pyridine ring formation step plays a key role. All the newly formed compounds were well characterized by spectral techniques such as FTIR, ¹HNMR, ¹³CNMR, HRMS and XRD. The potential therapeutic activities such as anti‐inflammatory activity by protein denaturation and RBC membrane stabilization methods, and anti‐oxidant activity by DPPH scavenging method of the newly synthesized compounds were studied. Interestingly, in‐vitro testing of these compounds reveals that the compounds 4d , 4g , 4i , 8a and 8b showed comparable anti‐inflammatory activity with respect to the standard drug, diclofenac. Similarly, fused pyridine 4f showed excellent anti‐oxidant activity when compared with the standard, ascorbic acid.     

Evaluation of anti‐angiogenic,anti‐inflammatory and antinociceptive activity of coenzyme Q10 in experimental animals

Objectives This work aimed to assess some pharmacological activities of coenzyme Q₁₀ (CoQ₁₀) in animal experimental models. Methods The chick chorioallantoic membrane assay was used to evaluate anti‐angiogenic activity of CoQ₁₀. Anti‐inflammatory activity of CoQ₁₀ was confirmed using two animal models of inflammation. These were the vascular permeability and air pouch models, models of acute and sub‐acute inflammation, respectively. Antinociceptive activity was assessed by the acetic acid‐induced abdominal constriction response. Key findings CoQ₁₀ dose‐dependently displayed inhibition of chick chorioallantoic membrane angiogenesis. In the acetic acid‐induced vascular permeability model in mice, CoQ₁₀ at 50, 100 and 200 mg/kg reduced vascular permeability from 0.74 ± 0.01 (A₅₉₀) to 0.67 ± 0.01 (P < 0.01), 0.46 ± 0.02 (P < 0.01) and 0.30 ± 0.01 (P < 0.01), respectively. In the carrageenan‐induced inflammation in the air pouch, CoQ₁₀ was able to diminish exudate volume, the number of polymorphonulcear leucocytes and nitrite content in the air pouches. CoQ₁₀ at 25, 50 and 100 mg/kg significantly reduced acetic acid‐induced abdominal constriction in mice from 27.0 ± 2.00 (number of abdominal constrictions) to 17.7 ± 0.33 (P < 0.01), 9.3 ± 0.67 (P < 0.01) and 1.3 ± 0.33 (P < 0.01), respectively, suggesting a strong antinociceptive activity. Conclusions CoQ₁₀ possessed considerable anti‐angiogenic, anti‐inflammatory and antinociceptive activity, possibly via down‐regulating the level of nitric oxide, which partly supported its use as a dietary supplement and in combination therapy.     

Preclinical pharmacokinetic and pharmacodynamic evaluation of thiazolidinone PG15: an anti‐inflammatory candidate

Objectives Novel 5‐benzilidene thiazolidinones have been synthesized and exhibited anti‐inflammatory activity. In this work one of the compounds of the thiazolidinone chemical series, (5Z,E)‐3‐[2‐(4‐chlorophenyl)‐2‐oxoethyl]‐5‐(1H‐indol‐3‐ ylmethylene)‐thiazolidine‐2,4‐dione (PG15) was investigated aiming to determine the drug's anti‐inflammatory potential in pre‐clinical studies. Methods Methods used included the in‐vitro inhibition of cyclooxygenase‐1 and ‐2, in‐vivo evaluation of anti‐inflammatory activity by air pouch and peritonitis models and the pharmacokinetic profile after intravenous (3 mg/kg) and oral (3 and 6 mg/kg) dosing to rats. Key findings A two‐compartment model with a fast distribution and an elimination half‐life of 5.9 ± 3.8 h described the PG15 plasma profile after intravenous dosing. PG15 showed an erratic and rapid absorption following oral administration with peak concentrations between 0.5 and 1 h. PG15 0.1 μM inhibited more than 30% and 13% of purified cyclooxygenase‐1 and ‐2 activity in vitro, respectively. A lack of dose dependency was observed for the anti‐inflammatory effect in the dose range investigated (0.8–50 mg/kg), with a maximum of 67.2 ± 4.6% inhibition of leucocyte migration in the carrageenan‐induced air pouch model obtained with the 3 mg/kg dose, similar to that observed for indometacin 10 mg/kg. Conclusions The erratic absorption of PG15 observed after oral dosing could explain the lack of anti‐inflammatory dose dependency.     

1H‐1,2,3‐Triazole tethered isatin‐moxifloxacin: Design,synthesis and in vitro anti‐mycobacterial evaluation

A series of novel 1H‐1,2,3‐triazole tethered isatin–moxifloxacin (MXF) hybrids 5a ‐ l with greater lipophilicity compared with the parent MXF were designed, synthesized and screened for their in vitro antimycobacterial activities against Mycobacterium tuberculosis (MTB) H₃₇Rv and multidrug‐resistant MTB (MDR–MTB) as well as their cytotoxicity on the VERO cell line. All the synthesized hybrids (MIC: 0.025‐0.78 μg/ml) showed considerable activities against MTB H₃₇Rv and MDR–MTB, and the most active conjugate 5c (MIC: 0.025 and 0.06 μg/ml) was 2 to >2048 times more potent in vitro than the three references MXF (MIC: 0.10 and 0.12 μg/ml), rifampicin (MIC: 0.39 and 32 μg/ml) and isoniazid (MIC: 0.05 and >128 μg/ml) against the two tested strains. All hybrids (CC₅₀: 4‐64 μg/ml) were much more cytotoxic than the parent MXF (CC50: 128 μg/ml), but the most active hybrid 5c (CC₅₀: 32 μg/ml) also displayed acceptable cytotoxicity, warranting further investigation.     

Curcumin‐loaded poly(ε‐caprolactone) nanofibres: Diabetic wound dressing with anti‐oxidant and anti‐inflammatory properties

• 1 Curcumin is a naturally occurring poly‐phenolic compound with a broad range of favourable biological functions, including anti‐cancer, anti‐oxidant and anti‐inflammatory activities. The low bioavailability and in vivo stability of curcumin require the development of suitable carrier vehicles to deliver the molecule in a sustained manner at therapeutic levels.
• 2 In the present study, we investigated the feasibility and potential of poly(caprolactone) (PCL) nanofibres as a delivery vehicle for curcumin for wound healing applications. By optimizing the electrospinning parameters, bead‐free curcumin‐loaded PCL nanofibres were developed.
• 3 The fibres showed sustained release of curcumin for 72 h and could be made to deliver a dose much lower than the reported cytotoxic concentration while remaining bioactive. Human foreskin fibroblast cells (HFF‐1) showed more than 70% viability on curcumin‐loaded nanofibres.
• 4 The anti‐oxidant activity of curcumin‐loaded nanofibres was demonstrated using an oxygen radical absorbance capacity (ORAC) assay and by the ability of the fibres to maintain the viability of HFF‐1 cells under conditions of oxidative stress.
• 5 The curcumin‐loaded nanofibres also reduced inflammatory induction, as evidenced by low levels of interleukin‐6 release from mouse monocyte–macrophages seeded onto the fibres following stimulation by Escherichia coli‐derived lipopolysaccharide.
• 6 The in vivo wound healing capability of the curcumin loaded PCL nanofibres was demonstrated by an increased rate of wound closure in a streptozotocin‐induced diabetic mice model.
• 7 These results demonstrate that the curcumin‐loaded PCL nanofibre matrix is bioactive and has potential as a wound dressing with anti‐oxidant and anti‐inflammatory properties.

     

In vitro evaluation of the effects of anti‐fungals,benzodiazepines and non‐steroidal anti‐inflammatory drugs on the glucuronidation of 19‐norandrosterone: implications on doping control analysis

We have studied whether the phase II metabolism of 19‐norandrosterone, the most representative metabolite of 19‐nortestosterone (nandrolone), can be altered in the presence of other drugs that are not presently included on the Prohibited List of the World Anti‐Doping Agency. In detail, we have evaluated the effect of non‐prohibited drugs belonging to the classes of anti‐fungals, benzodiazepines, and non‐steroidal anti‐inflammatory drugs on the glucuronidation of 19‐norandrosterone. In vitro assays based on the use of either pooled human liver microsomes or specific recombinant isoforms of uridine diphosphoglucuronosyl‐transferase were designed and performed to monitor the formation of 19‐norandrosterone glucuronide from 19‐norandrosterone. Determination of 19‐norandrosterone (free and conjugated fraction) was performed by gas chromatography – mass spectrometry after sample pretreatment consisting of an enzymatic hydrolysis (performed only for the conjugated fraction), liquid/liquid extraction with tert‐butylmethyl ether, and derivatization to form the trimethylsilyl derivative. In parallel, a method based on reversed‐phase liquid chromatography coupled to tandem mass spectrometry in positive electrospray ionization with acquisition in selected reaction monitoring mode was also developed to identify the non‐prohibited drugs considered in this study. Incubation experiments have preliminarily shown that the glucuronidation of 19‐norandrosterone is principally carried out by UGT2B7 (39%) and UGT2B17 (31%). Inhibition studies have shown that the yield of the glucuronidation reaction is reduced in the presence of the anti‐fungals itraconazole, ketoconazole, and miconazole, of the benzodiazepine triazolam and of the non‐steroidal anti‐inflammatory drugs diclofenac and ibuprofen, while no alteration was recorded in the presence of all other compounds considered in this study. Copyright © 2015 John Wiley & Sons, Ltd.     

High specific activity tritium labeling of anti‐tumor agent CEP‐2563

[Ester Methylene‐³H] CEP‐2563 ( 9 ) was synthesized by the tritiation of precursor 6 with NaB³H₄ followed by esterification with BOC‐Lys(BOC)‐β‐Ala‐OH and deprotection. Copyright © 2005 John Wiley & Sons, Ltd.     

One‐pot cascade synthesis and in vitro evaluation of anti‐inflammatory and antidiabetic activities of S‐methylphenyl substituted acridine‐1,8‐diones

Various S‐methylphenyl substituted acridine‐1,8‐dione series ( 4a–i ) were synthesized through a one‐pot cascade synthetic approach involving the reaction of 4‐(methylthio)benzaldehyde and dimedone with a variety of amines as nitrogen source under reflux in ethanol. All the synthesized derivatives were characterized by using spectroscopic methods. In vitro evaluations of anti‐inflammatory and antidiabetic efficacies of all the synthesized compounds were investigated. The anti‐inflammatory results infer that the compounds 4c and 4d are showing excellent activity with an inhibition percentage of 80.58 ± 0.42, 81.72 ± 1.72 by membrane stabilization and 77.72 ± 0.76, 78.76 ± 0.81 by albumin denaturation methods, which is comparable with the standard diclofenac at a concentration of 100 μg/ml. Further, the antidiabetic assay revealed the moderate activity for the synthesized compounds at a concentration of 100 μg/ml with respect to their standard drug, acarbose.